Module and apparatus for synthesis of organic molecules or the like

ABSTRACT

The invention concerns a module for the synthesis of organic molecules on or in solid phase and an apparatus comprising at least such a module. Said module is characterised in that it mainly consists of several synthesis reactors ( 2 ) formed, each, by a tubular body ( 3 ) forming a reaction chamber ( 3′ ) delimited in its lower part by a removable porous wall ( 4 ), designed to retain the synthesis support material, an injection and expanding head ( 5 ) forming an upper closure plug for the tubular body ( 3 ), a closure and emptying base ( 6 ) mounted removable in a lower extension ( 3″ ) of the tubular body ( 3 ), each reactor ( 2 ) being provided with a heat exchanger ( 7 ) in close peripheral contact with the tubular body ( 3 ) at least at the part ( 3′″ ) of the chamber ( 3′ ) designed to contain the medium and the reaction compounds and a condenser ( 8 ) in close peripheral contact with the body ( 3 ) at the part ( 3″″ ) of the chamber ( 3′ ) extending above that ( 3 ′″) containing the medium and the reaction compounds and beneath the injection head ( 5 ), and said assembly of reactors ( 2 ) being mounted in an isolating structure ( 9 ) enclosing said reactors ( 2 ) at least at said heat exchangers ( 7 ) and said condensers ( 8 ).

[0001] The present invention relates to the field of synthesis ofmolecules, in particular organic, particularly in solid phase and inlarge number, and has for its object a module for the conduct of suchsyntheses, as well as an apparatus comprising at least one such module.

[0002] From EP-A-0 208 641, there is already known a semiautomaticmulti-synthesizer of peptides in solid phase, comprising a plurality ofindividual reactors each connected to a volumetric measure and disposedto form several independent parallel synthesis paths. This apparatus canuse only a single synthesis chemistry, either BOC, or Fmoc, and usesexclusively the so-called Merifield technique. Said reactors aredisposed in open air and their parallel spaced arrangement results in alarge total size.

[0003] Then, from FR-A-2 664 602, there is known a robot for thesimultaneous synthesis of several identical or different peptides insolid phase.

[0004] This robot comprises a plurality of non-isolated reactorsgathered on several plates and comprises mechanized movable means forthe preparation and injection of solvents and amino acids.

[0005] There results an apparatus of complicated structure requiringcontinuous maintenance.

[0006] It should be noted that none of the above apparatus comprisesmeans for controlling the temperature in the different reactors, nor foradjustment of said temperature as a function of the reactions inprogress or to be initiated.

[0007] Moreover, an important multiplication of reactors in thementioned apparatus for increasing performance, gives rise to aproportional increase in the complexity of the structure of theapparatus and the size of this latter, incompatible with laboratory useand requiring a rearrangement of the internal construction andarrangement of said apparatus.

[0008] Finally, the mentioned apparatus provide for decompacting, mixingand suspending in the present medium in said injection reactors, gas tocarry out bubbling, which of course avoids the destruction of thesupport and the synthesis products, but can also prove to beinsufficient in the case of important and intimate agglomeration anddoes not permit guaranteeing good homogeneity to a suspension of thesolid/liquid medium in the different reactors.

[0009] The present invention has particularly for its object to overcomeat least certain of the drawbacks mentioned above and to provide asolution permitting carrying out simultaneous syntheses of molecules, inparticular organic ones, in solid phase, according to various methods orstrategies of synthesis, in separate synthesis containers and subjectparticularly to identical and controlled physical or thermodynamicconditions, whilst permitting easy access to the interiors of saidreactors and a modular association of a large number of synthesiscontainers without producing too complicated a structure.

[0010] To this end, the present invention has for its object a modulefor the synthesis of molecules that are organic or not, on or in solidphase, principally constituted by several, preferably at least two andat most ten, separate synthesis reactors, arranged according to acircular arrangement with equi-angular distribution and each formed of atubular body forming a reaction chamber delimited in its internalportion by a removable porous wall, adapted to retain the materialforming the synthesis support, by an injection and expansion headforming an upper closure plug for the tubular body, and by a closing andemptying base mounted removably in lower prolongation of the tubularbody and ensuring peripheral sealed holding of the retention wall, eachreactor being provided with a heat exchanger in intimate peripheralcontact with the tubular body at least at the level of the portion ofthe chamber adapted to contain the medium and the reaction compounds andby a condenser in intimate peripheral contact with the body at the levelof a portion of the chamber extending above that containing the mediumand the reaction components and below the injection head, and saidassembly of reactors being mounted in an insulating structuresurrounding said reactors at least at the level of said exchangers andsaid condensers, the action of these latter being similar for all thereactors of the module and the insulation being homogeneous for all thereactors, such that said reactors will be subjected permanently toidentical thermal conditions.

[0011] It also has for its object an apparatus for the synthesis oforganic molecules in solid phase, operating automatically orsemi-automatically, comprising at least one module of the mentionedtype.

[0012] The invention will be better understood from the followingdescription, which relates to a preferred embodiment, given by way ofnon-limiting example, and explained with reference to the accompanyingschematic drawings, in which:

[0013]FIG. 1 is a partial side elevational view of a module according tothe invention, without insulating structure, comprising only tworeactors of which one has no base and the other no injection head andsurmounted by the support structure carrying the rotatable agitationmembers and their drive members;

[0014]FIG. 2 is a view similar to that of FIG. 1 showing moreparticularly the exchanger and condenser and the assembly and supportstructure;

[0015]FIG. 3 is a view similar to that of FIG. 2 showing moreover theinsulating structure;

[0016]FIG. 4 is a top plan view of the object shown in FIG. 2;

[0017]FIG. 5 is a bottom plan view of the object shown in FIG. 2;

[0018]FIGS. 6A and 6B are respectively views from above and inlongitudinal cross-section of a tubular body of a reactor;

[0019]FIG. 7 is a detailed view, on a different scale, of the base shownin FIG. 1;

[0020]FIGS. 8A, 8B and 8C are respectively views in side elevation, fromabove, and from below, of the injection head shown in FIG. 1;

[0021]FIG. 9A is a top plan view of the support structure and of thedrive members for the rotatable agitation members shown in FIG. 1 andFIG. 9B is a schematic representation from above showing the arrangementof the movement transmission members, for example in the form of belts,for the rotatable agitation members of FIG. 1;

[0022]FIG. 10 is a synoptic representation of a synthesis apparatusaccording to the invention;

[0023]FIG. 11 is a cross-sectional and side elevational view of thetubular body and the base of a container forming an exchange anddistribution chamber and forming a portion of the synthesis apparatusshown in FIG. 10;

[0024]FIG. 12 is a side elevational view by transparency and partiallyin cross-section, of an exchanger/condenser/insulating structureassembly for a container of the type shown in FIG. 11, and

[0025]FIG. 13 is a side elevational view of the container of FIG. 11provided with an injection head and a drive mechanism for the agitatingmember.

[0026] As shown more particularly in FIGS. 1 to 5 of the accompanyingdrawings, the module 1 for the synthesis of molecules, in particularorganic ones, on a solid phase, for example on resin, has a compact andsmall structure, with optimum, regular and homogeneous arrangement ofits different constituent elements, particularly of its reactors.

[0027] According to the invention, this module 1 is essentiallyconstituted by several, preferably at least two and at most ten,separate synthesis reactors 2, arranged in a circular arrangement withequi-angular distribution and each formed by a tubular body 3 forming areaction chamber 3′ delimited in its lower portion by a removable porouswall 4, adapted to retain the material forming the synthesis support, byan injection and expansion head 5 forming an upper closure plug for thetubular body 3, and by a closure and emptying base 6 mounted removablyin lower prolongation 3″ of the tubular body 3 and ensuring theperipheral sealed holding of the retention wall 4, each reactor 2 beingprovided with a heat exchanger 7 in intimate peripheral contact with thetubular body 3 at least at the level of the portion 3′″ of the chamber3′ adapted to contain the medium and the reaction compounds, and by acondenser 8 in intimate peripheral contact with the body 3 at the levelof a portion 3″″ of the chamber 3′ extending above the portion 3′″containing the medium and the reaction components and below theinjection head 5, and said assembly of reactors 2 being mounted in aninsulating structure 9 surrounding said reactors 2 at least the level ofsaid exchangers 7 and said condensers 8, the action of these latterbeing similar for all the reactors 2 of the module 1 and the insulationbeing homogeneous for all the reactors 2, such that said reactors 2 willbe continuously subjected to identical thermal conditions.

[0028] Preferably, the module 1 will comprise between three and sevenreactors 2, each of these latter having for example an internal volumeof about 60 ml for a useful volume of about 20 ml.

[0029] As shown in FIGS. 4 and 5 of the accompanying drawings, thesereactors are arranged according to a circular arrangement and withequi-angular distribution (constant angular spacing between twoneighboring reactors).

[0030] Each tubular body 3 will have a sufficiently small thickness toensure rapid thermal transmission between the exchanger 7 and thecondenser 8 mounted on the exterior of said body and the interior ofthis latter, and a length sufficient to permit a large temperaturegradient between the wall portions in contact with the reaction mediumand the ends of said bodies in contact with the base 6 and the injectionhead 5, with limited loss by longitudinal transmission.

[0031] The tubular body 3, as well as its prolongation 3″ formed in asingle piece with it, will be made of a material resistant to a widerange of negative and positive temperatures, to variations and gradientsof temperature of large value, as well as to the reaction substances andto the products derived or synthesized that may be obtained.Polytrifluorochlorethylene satisfies the mentioned criteria and couldfor example form the body 3 and its prolongation 3″ as well as theinjection head 5 and the portions of the base 6 in contact with thereaction medium.

[0032] To be able to carry out effective condensation in associationwith substantial heating, the condenser 8 and the exchanger 7 of a samereactor 2 are physically separated and mounted on this latter withmutual longitudinal spacing, as the case may be with interposition of aninsulating material, and connected to lines 10, 11 for supply andevacuation of separate heat exchange liquid or liquids, the temperatureof the fluid, preferably liquid, for the condensers 8 being adapted tovary from ambient temperature to about 15° C. (for example waterdelivered by the public distribution network) and the temperature ofgaseous fluid for the exchanger 7 can vary between about −80° C. andabout −100° C., which permits establishing ideal temperature conditionsfor all the usual reactions in organic chemistry.

[0033] According to a preferred embodiment of the invention, shown inFIGS. 1, 2 and 3 of the accompanying drawings, the condensers 8 and theexchangers 7 are each constituted by a plurality of helicoidal adjacentturns of a metallic conduit of rectangular or square cross-section, thefittings 7′, 8′ for supply and evacuation of all the condensers 8 andexchangers 7 being radially inwardly directed of the circulararrangement formed by the assembly of reactors 2 and connected tocentral portions 10′, 11′ for radial connection and distribution ofsupply and evacuation lines 10, 11 of heat exchange fluid or fluids, thesupply and evacuation lines 10, 11 being connected at their centralconnection and distribution portions 10′, 11′ on the two oppositesurfaces or sides 1′, 1″ of said module 1 and the configuration of saidcentral portions 10′, 11′ giving rise to equivalent pressure drops andequivalent circulation paths, on the one hand, for all the condensers 8,and, on the other hand, for all the exchangers 7.

[0034] The different exchangers 7 and condensers 8 with their respectivecentral portions 10′ and 11′ will constitute two circulation circuits offluids, with a rigid structure.

[0035] The supply and evacuation lines 10 connected to the centralportions 10′ are thermally insulated and could for example consist oflines known by the term “dewar”.

[0036] The connection of the lines 10 to the connection fittings of thecentral portions 10′ could for example be carried out by means of aself-blocking and thermal insulating holding and securement assembly asshown in FIG. 2. This assembly comprises a casing 10″ secured to thecorresponding fitting and provided with a truncated conical openingadapted to receive the end of a conduit of the line 10. An annularinsert 10′″, of wedge shaped cross-section, and for example in twoparts, is forcibly inserted between the conduit and the internal surfaceof the opening of the casing under the action of a nut 10″″ engaging onexternal screw threading provided on the casing 10″ (see FIG. 2).

[0037] The insert 10′″ consists of a rigid material with thermalinsulating properties and the mentioned mounting ensures the holding andblocking of the conduit of the line 10, as well as a rigidification ofthe structure of the assembly of the module 1.

[0038] A central supply relative to the reactor assembly 2 permitsobtaining equal distribution between the different exchangers 7 andcondensers 8 and hence equivalent heat transfers at the level of thedifferent reactors 2.

[0039] Moreover, the opposite supply connection directions (FIG. 2:downwardly for the exchangers 7 and upwardly for the condensers 8)avoids any contact between the two circulation circuits and prevents anydisturbing heat transfer between them.

[0040] Preferably, the exchangers 7 and condensers 8, with theirconnection and distribution portions 10′, 11′, could be made of nickelcopper.

[0041] As shown in FIGS. 3 to 5 of the accompanying drawings, the module1, and more particularly the insulating structure 9, has an externalshape of a flat cylinder, permitting access to the bases 6 and leavingthe injection heads 5 exposed. Said structure is mounted and comprisedbetween two separate parallel disc-shaped plates 12′ connected by crossmembers 12″ and forming together an assembly and support structure 12 onwhich are mounted the tubular bodies 3 of the synthesis reactors 2, saidstructure 12 being, as the case may be, covered or surroundedperipherally or over all its external surface, with a film, a sheet, aplate or the like of material that reflects thermal radiation and havingvapor protective properties and said structure 12 carrying if desiredsaid exchangers 7 and/or condensers 8 and/or a portion of their supplyand evacuation lines 10, 11.

[0042] The latter could, particularly as to the supply lines, and as thecase may be the evacuation lines of the exchanger 7, be preferentiallythermally insulated over all their length and the connection with thecentral connection and distribution portions 10′ could take place withinthe mass of the insulating structure 9 to limit outward losses (see FIG.3).

[0043] The disc-shaped plates 12′ could, as the case may be, also becovered with a vapor-resistant material.

[0044] According to one embodiment of the invention, shown moreparticularly in FIG. 3, the insulating structure 9 is constituted, onthe one hand, by portions of rigid insulating material 9′, for examplepolyisocyanurate foam, peripherally surrounding the assembly of reactors2 and forming substantially a ring about this latter, and, on the otherhand, by an insulating material 9″ that is pulverulent or formed ofballs of small diameter, for example of perlitic rhyolite, contained inthe ring formed by the portions of rigid insulating material 9′ andfilling the free volumes between the bodies 3 of the different reactors2, the exchangers 7 and the condensers 8, the assembly of the exchangers7, and the case may be, the assembly of the condensers 8, being adaptedto be surrounded peripherally by one or several layers of ceramic cloth9′″, forming insulating protective walls between these elements 7, 8 andthe internal surface of the ring of rigid insulating material 9′, theexchangers 7 being, as the case may be also sandwiched between two discs9′″ of ceramic cloth so as completely to enclose said exchangers in acocoon of ceramic cloth.

[0045] The insulating walls formed by the ceramic cloth (for example ofthe Fiberfrax Paper type—trademark) permit generating a temperaturedifferential between the exchangers 7/condensers 8 and the portions ofrigid insulating material 9′ which, in addition to the supplementalinsulation that is obtained, will avoid subjecting these latter to toogreat temperatures.

[0046] As a modification, there can be provided to pour a suitableinsulating foam material between the disc-shaped plates 12′ and thereactors 2, which material upon expanding will fill all the emptyvolumes between the constituent elements.

[0047] As shown in FIGS. 1, 2, 4, 6A, 6B and 7 of the accompanyingdrawings, each tubular body 3 comprises, on the one hand, at the levelof its interface with its lower prolongation 3″, a projecting internalring 13 forming a circumferential abutment for blocking and peripheralsealing gripping of the retention wall 4 of the material forming asynthesis support, for example in the form of a disc-shaped filter, and,on the other hand, several longitudinal conduits 14, 14′, 14″ forinjection or passage, hollowed within the thickness of its wall andextending from the upper edge of said body 3, or at least from an upperportion of the body 3 located beyond the insulating structure 9, to thelevel of the portion 3′″ of the reaction chamber 3′ adapted to containthe reaction medium and compounds, opening or not above said projectinginternal ring 13 has an annular hollowed reinforcement 14′″ or formed insaid wall.

[0048] Among the mentioned conduits distributed circumferentially in thewall of the body 3, at least two serve for conveying substances that areto be delivered directly into the portion 3′″ of the chamber 3′containing the reaction medium, slightly above the woven filter formingthe porous retention wall 4.

[0049] Thus, one 14 of the conduits could serve for the injection of theresin that supports synthesis (the conduit 14 will have a diametersuitable to this injection and will avoid stoppering of other conduitsor of the injection head 5), another 14′ for the injection of thesynthons and/or the coupling reagents (injection without loss ofsubstances in small quantity and delivering without pollution directlyinto the medium). A third conduit 14″ will serve for the introduction ofa monitoring member for the temperature of the reaction medium, such asa filamentary thermocouple. This conduit 14″ will not be plugged andwill extend preferably to a distance permitting positioning of themeasuring head in a median position relative to the reaction medium.

[0050] It will be noted that the construction of the conduits 14 and 14′permits effective and complete cleaning by simple injection of solventthrough them (absence of external surface, no portion unexposed to theflow). Moreover, the unstoppering of the conduits 14, 14′ adjacent thefilter 4 permits evacuation of most of the medium through these conduitsduring gaseous pressurization of the chamber 2′, without risk of closure(particularly for the conduit 14).

[0051] The mentioned conduits could preferably communicate at theirupper ends through lateral or radial conduit portions associated withsupply sites or fittings 14″″ (FIG. 1).

[0052] To obtain sealed closure in the lower portion of the reactor,whilst having the possibility of freeing and opening in the prolongation3″ over all the width of this latter and of being able rapidly toexchange the porous retention wall 4, each base 6 is preferablyconstituted, on the one hand, by a bearing and sealing ring 15 mountedwith locked adjustment and blockage in translation in the direction ofthe upper portion of the reactor 2 in question, for example against aprojecting internal ring 13, in tubular prolongation 3″ of the tubularbody 3 of said reactor 2 and provided with at least one circumferentialrib 15′ for peripheral gripping of the wall 4, on the other hand, by asupport and compression body 16 for the compressible porous retentionwall 4 comprising, on the side directed toward said wall 4, a flatexternal circumferential bearing surface 16′ facing the rib or ribs 15′of the ring 15 and an internal conical surface 16″ inclined toward acentral evacuation opening 17 connected to an axial emptying channel 17′hollowed out in said body 16 and provided with protuberances 18 forsupporting the porous retention wall 4 and, finally, by a removableassembly 19, 20 for locking the support and compression body 16 againstthe support ring 15 and the connection of a conduit or tubing to theoutlet of the emptying channel 17′ (FIGS. 1 and 7).

[0053] The inwardly projecting ring 13 could be formed at the interfaceof the tubular body 3 and its lower prolongation 3″, the ring 15 beingforcibly mounted in said prolongation 3′ and the body 16 having anexternal flange coming into coacting engagement with an external recessof complementary shape formed at the lower edge of said ring 15.

[0054] It will be noted that the axial emptying channel 17′ could, asthe case may be, be used for injection of gas for bubbling purposes.

[0055] Moreover, said channel 17′ could also serve for the extraction ofthe synthesis products after their cleavage on the synthesis support.

[0056] As also shown in FIG. 7 of the accompanying drawings, theremovable gripping assembly could be comprised by a member 19 forguidance and transmission of the pressure forces between a nut 20,preferably double screw-threaded and with a Z-shaped cross-section,engaging by screwing with a screw-threaded casing 21 secured to theprolongation 3″ of the tubular body 3 and the support and compressionbody 16 of the retention wall 4, comprising a first hollow cylindricalportion 22 coming into contact, shape-matingly, against the rear surfaceof the support and compression body 16 by axially guiding a rearprolongation 16′″ of said body 16 on which is mounted a connectionmember 23 of a connection fitting 23′ of a conduit or tube adapted to beconnected to the axial emptying channel 17′, and a second cylindricalportion 22′ comprising a portion forming a washer interposed between thefirst cylindrical portion 22 and a force application surface 20′ of thenut 20 and a cylindrical portion prolonging said portion forming awasher and ensuring the guidance of the nut 20 relative to the member 19for guidance and transmission of forces and for holding and guiding anadjacent portion of the conduit or tube connected to the axial emptyingchannel 17′.

[0057] If desired, a force transmission washer 20″ could be providedbetween the surface 20′ of the nut 20 and the second cylindrical portion22′, this latter being adapted to receive on its end extending beyondthe nut 20, a circlip or stop 20′″ engaged by said nut during itsunscrewing and driving the second and first hollow portions 20 and 20′,trapping the connection fitting 23′, this latter in turn driving themember 23 and the body 16 with the same retraction movement.

[0058] According to a characteristic of the invention and as shown inFIGS. 1 and 8 of the accompanying drawings, the injection head 5preferably comprises, on the one hand, an axial through passage 24 forthe mounting with ease or rotation of an element in the form of a rod30′, on the one hand, a principal injection channel 25 that is eccentricand connected upstream to several supply channels 26, 26′, 26″prolonging lateral sites 27 for connection of conduits or tubes fordelivering fluid or fluids and opening into said injection channel 25 atpositions offset along this latter and, downstream, to radialdistribution channels 28 extending from the downstream end of saidinjection channel 25 and opening adjacent the upper edge of the internalsurface of the wall of the upper portion of the tubular body 3 of thereactor 2 in question, with regular distribution and substantiallyequivalent pressure drops, and, finally, by an eccentric channel 29 forexpansion and evacuation of the gaseous fluids, opening on the lowersurface of the injection head 5 and connected to a lateral site 29′ forcorresponding external connection.

[0059] Such an embodiment of said channels 28 permits carrying outparticularly, by distributed injection of suitable solvent, a washing byaspersion and leaching of all of the internal surface of the wall of thetubular body 3.

[0060] To obtain substantially equal pressure drop for the differentchannels 28, these latter will have diameters proportional to theirlengths (constant length/diameter ratio).

[0061] The supply channel 26 opening farthest upstream (relative to thedirection of injection) on the principal injection channel 25, willpreferably be reserved for the injection of the solvent, particularlythe washing and rinsing solvent, which will permit cleaning the channel25 over all its length and provided liquid plugs in this latter, thesupply channels 26, 26′ and 26″ and the channels 28 can be maintainedduring all the duration of one phase or of one synthesis procedure,limiting the retro contaminations and being adapted to be injected intothe chamber 3′ after the synthesis phase under the pressure of aquantity of supplemental solvent.

[0062] The supply channel 29 will serve the principal office ofexpansion outlet for the gases present or forming during synthesisreactions, and, as the case may be, for the pressurizing channel of thechamber 3′ during expulsion and extraction of the products contained inthis latter.

[0063] The pressurization of the reactor 2 can also be carried out bymeans of the solvent injection channel 26, which moreover offers theadvantage of easy cleaning and the possibility of emplacement of liquidplugs.

[0064] To be able to actuate the reaction by mixing, this agglomerationof the decanted and homogenized substances of the reaction medium, nomatter what the condition of agglomeration of this latter, each reactor2 is provided with a rotating member 30 for mechanical agitation of themedium or mixture contained in the reaction chamber 3′ in question, inthe form of a helix located at a small distance above the retention wall4 of the synthesis support and mounted on the end of a rod 30′ forming ashaft or axle passing through the injection head 5 at the level of anaxial passage 24 adapted and provided at its opposite end with a notchedpulley 30″ or with similar element for its driving by a member 31′ fortransmission and distribution of movement, for example of the notchedbelt type, interconnecting the pulleys 30′ of the agitation members 30of the different reactors 2 of the module 1, the synchronous rotation ofthe different agitation members 30 being assured by a variable speedmotor 32 directly or indirectly driving said transmission anddistribution member 31 and mounted, together with said pulleys 30″ andsaid member 31, as well as if desired with the return pulleys and one ormore belt tighteners 33, 33′ on a suitable support structure 34, in aremovable manner, on the module 1 (FIGS. 1, 9A and 9B).

[0065] The blades of the helix 30 are preferably inclined to have alower edge located forwardly relative to the direction of rotation ofsaid helix 30, as well as the lower portion of the rod 30′, particularlythat immersed in the reaction medium, are clad with a chemicallyresistant and thermally insulating material.

[0066] It will be noted that the use of a helix 30 slightly offsetrelative to the surface of the wall 4 and adapted to be driven atdifferent speeds, permits more effective decompacting than a simplebubbling whilst not scraping the synthesis support and the productswhich are attached thereto, as a magnetic barrel would.

[0067] The rod 30′ will of course be mounted at the level of the axialpassage 24 in hermetically sealed bearings.

[0068] As shown in FIGS. 1 and 9B of the accompanying drawings, themotor 32 could, to reduce the overall size, be disposed between thesupport structure 34, for example in the form of a plate, and the upperdisc-shaped plate 12′ of the support structure 12 of the module 1 andthe transmission would take place in two stages, a first stagecomprising a primary belt 31 for transmission between the axle or shaftof the motor 32 and a principal drive pulley or the return mountedcoaxially on a rod 30′ with a secondary pulley 30″ offsetlongitudinally, said secondary pulley 30″ transmitting the movement tothe other pulleys 30″ (mounted on rods 30′ provided with members 30) bythe transmission member 31′ (distribution belt) and forming with themand this latter the second transmission stage.

[0069] The support structure 34, as well as the constituent elements ofthe support structure 12, could for example be made of aluminum or ananodized aluminum alloy.

[0070] The module 1 described above and of which one embodiment is shownin FIGS. 1 and 9 of the accompanying drawings, is adapted to constitutethe fundamental modular element of a synthesis apparatus for organicmolecules or the like, alone or in association with other modules 1 ofthe same type.

[0071] Those skilled in the art will particularly notice the polyvalenceof use of such a module 1 in terms of technique or synthesis protocolthat can be carried out (combination chemistry, parallel or the like)and of varieties of environmental materials that can be constructedabout such a module or modules (injection circuits, emptying circuits,expansion circuits, pressurizing circuits, heating circuits, coolingcircuits, refrigeration circuits, . . . ).

[0072] Thus, as to the nature of connections and destination of theinjection sites, supply sites and evacuation sites are respected, saidmodule 1 could serve as an instrument or tool for synthesis in verydiverse applications.

[0073] The present invention also has for its object an apparatus forthe synthesis of organic molecules in solid phase, with automatic orsemiautomatic functioning comprising at least one module 1 as previouslydescribed.

[0074] As shown schematically in FIG. 10 of the accompanying drawings,in such an apparatus said module or modules 1 could, for example, in anon-limiting embodiment, be connected, on the one hand, at the level ofthe reactors 2, of the reservoirs 35, 36, 37, 38, 39, 40 for solvents,compounds or elemental substances for syntheses, synthesis supportsubstances, reagents, substances for emptying, for recovering of waste,for expansion or the like, by means of a distribution and transfernetwork constituted by a network of conduits or tubes 41′ interconnectedwith single path or multi-path units 41 of membrane valves, alsointegrating volumetric measures 42, the movement of the fluids in saidnetwork taking place under the action of gas under pressure, for exampleargon or nitrogen, whose application for pressurizing different fluidsegments is controlled by predetermination sequential actuations ofsuitable valve units 41, the opening times of said valves determiningthe volumes transferred, and, on the other hand, in the exchangers 7 andcondensers 8, supply units 43, 43′ for heat exchange cooling or heatingfluid or fluids by suitable supply circuits formed by supply andevacuation lines 10, 11, said apparatus comprising moreover a computerunit 44 for control and management of the actuation of the differentunits of membrane valves 41 and of the operation of the supply units 43,43′ for gaseous heat exchange fluid or fluids, by means of suitableinterface and multiplexing circuits 44′ permitting effecting parametersin terms of sequences of synthesis and a selection between entirelyautomatic operation or semiautomatic operation, step by step, of saidapparatus.

[0075] For reasons of simplicity and ease of comprehension, FIG. 10 ofthe accompanying drawings shows only a single reactor 2, it being notedthat each reactor 2′ of a module 1 will have similar connections.

[0076] In FIG. 10, there will be seen particularly:

[0077] various reservoirs 35 for de-protection reagents or the like;

[0078] various reservoirs 36 for synthons, secondary synthons andcoupling reagents;

[0079] one or more reservoirs 37 for collecting waste, associated with aseparation and extraction unit for the liquid phase (not shown);

[0080] an inlet/outlet system 38 for the synthesis support resinconnected to the conduit 14 (the introduction of fresh resin at thebeginning, cleavage, mixing/distribution, transfer . . . );

[0081] reservoirs 39 for washing solvents;

[0082] an expansion reservoir 40;

[0083] a reservoir or source 46 of inert gas under pressure, for thetransfer by gaseous pressure of the fluids in the different distributionand emptying circuits under pressure of the different containers, theconnections between this source or reservoir 46 not being shown forreasons of simplicity.

[0084] In FIG. 10 are also not shown the interface for dialogue andprogramming of the computer unit 44, the various connections of thecircuits 44′ with different control members (particularly the valveunits 41), different monitoring modules (monitoring the reflux,temperature or the like), necessary for the automatic functioning of theapparatus, and whose construction is known to those skilled in the art.

[0085] A structure of synthesis apparatus for molecules that can serveas a base for the design and production of a structure of apparatusaccording to the invention is in particular described in French patentapplication No. 2 664 602 mentioned above, particularly with respect toFIGS. 2 and 3 of this latter.

[0086] Moreover, the valve units 41 will preferably have a constructionsimilar to that described and shown in French patent application No. 2664 671.

[0087] Preferably, the computer unit 44 also monitors the operation ofthe motor 32 driving the mechanical agitation members 30 in the form ofhelices, with controlled operation at at least two different speeds ofrotation, namely a low speed for suspension and homogenization of thereaction mixture and a high speed for generating of a vortex adapted toensure decompacting of the synthesis support.

[0088] The generation of a vortex will permit the choice of agglomerantspresent among themselves and against the internal wall of the reactionchamber 3′ a gentle and progressive de-agglomeration, without breakingor scraping.

[0089] As shown in FIGS. 10 to 13 of the accompanying drawings andaccording to a supplemental characteristic of the invention, thesynthesis apparatus could moreover comprise several modules 1 and inthat each module 1 is associated with a container 45 forming an exchangeand distribution chamber, whose internal volume corresponds to the sumof the internal volumes of the reactors 2 of the module 1 with which itis associated, whose construction is identical to those of said reactors2 except for the size of the constituent elements, can be connected tosaid reactors 2 by a portion of the distribution and transfer networkcomprising at least one multi-path unit 41 of membrane valves and, asthe case may be, provided with a mechanical agitation member 30, with aheat exchanger 7, a condenser 8 and thermal insulation over at least aportion of its tubular body 3.

[0090] In FIGS. 11 to 13, the constituent elements of the container 45corresponding to the analogous constituent elements of a reactor 2, havethe same reference numerals as the latter, although their shape,configuration and dimensions can be different.

[0091] Of course, the invention is not limited to the embodiment shownand described in the accompanying drawings. Modifications remainpossible, particularly as to the construction of the various elements orby substitution of technical equivalents, without thereby departing fromthe scope of protection of the invention.

1. Module for the synthesis of molecules, particularly organic, on or insolid phase, characterized in that it is principally constituted byseveral, preferably at least two and at most ten, separate synthesisreactors (2), arranged in a circular arrangement with equi-angulardistribution and each formed by a tubular body (3) forming a reactionchamber (3′) delimited in its lower portion by a removable porous wall(4), adapted to retain the material forming a synthesis support, by ahead (5) for injection and expansion forming an upper closure plug forthe tubular body (3), and by a base (6) for closing and emptying,mounted removably in a lower prolongation (3″) of the tubular body (3)and ensuring the peripheral sealed holding of the retention wall (4),each reactor (2) being provided with a heat exchanger (7) in intimateperipheral contact with the tubular body (3) at least at the level ofthe portion (3′″) of the chamber (3′) adapted to contain the medium andthe reaction compounds, and by a condenser (8) in intimate peripheralcontact with the body (3) at the level of a portion (3″″) of the chamber(3′) extending above the latter (3′″) containing the medium and thereaction compounds and below the injection head (5), and said assemblyof reactors (2) being mounted in an insulating structure (9) surroundingsaid reactors (2) at least at the level of said exchangers (7) and saidcondensers (8), the action of these latter being similar for all thereactors (2) of the module (1) and the insulation being homogeneous forall the reactors (2), such that said reactors (2) will be continuouslysubject to identical thermal conditions.
 2. Module according to claim 1,characterized in that it comprises between three and seven synthesisreactors (2) and in that the condenser (8) and the exchanger (7) of asame reactor (2) are physically separated, as the case may be withinterposition of an insulating material, and connected to supply andevacuation lines (10, 11) for separate heat exchange fluid or fluids,the temperature of the fluid, preferably liquid, for the condensers (8)being adapted to vary from ambient temperature to about 15° C. and thetemperature of the gaseous fluid for the exchangers (7) being adapted tovary between about −80° C. and about +100° C.
 3. Module according to anyone of claims 1 and 2, characterized in that the insulating structure(9) has an external flattened cylindrical shape, permitting access tothe bases (6) and leaving the injection heads (5) exposed, and iscomprised between two parallel separated disc-shaped plates (12′)connected by cross-members (12″) and together forming an assembly andsupport structure (12) on which are mounted the tubular bodies (3) ofthe synthesis reactors (2), said structure (12) being, as the case maybe, covered or surrounded peripherally or over all its external surfacewith a film, a sheet, a plate or the like of material that reflectsthermal radiation and having vapor-resistant properties and saidstructure (12) carrying if desired said exchangers (7) and/or condensers(8) and/or a portion of their supply and evacuation lines (10, 11). 4.Module according to any one of claims 1 to 3, characterized in that theinsulating structure (9) is constituted, on the one hand, by portions ofrigid insulating material (9′), for example polyisocyanurate foam,peripherally surrounding the assembly of reactors (2) and formingsubstantially a ring about this latter, and, on the other hand, by aninsulating material (9″) that is pulverulent or formed of balls of smalldiameter, for example of perlitic rhyolite, contained in the ring formedby the portions of rigid insulating material (9′) and filling the freevolumes between said bodies (3) of the different reactors (2), theassembly of exchangers (7), and as the case may be, the assembly ofcondensers (8), being adapted to be surrounded peripherally by one orseveral layers of ceramic cloth (9′″), forming insulating protectivewalls between these elements (7, 8) and the internal surface of the ringof rigid insulating material (9′), the exchangers (7) being, as the casemay be, also sandwiched between two discs (9′″) of ceramic cloth so ascompletely to enclose said exchangers (7) in a cocoon of ceramic cloth.5. Module according to any one of claims 1 to 4, characterized in thatthe condensers (8) and the exchangers (7) are each constituted by aplurality of adjacent helicoidal windings of a metallic conduit withrectangular or square cross-section, the fittings (7′, 8′) for supplyand evacuation of all the condensers (8) and exchangers (7) beingdirected radially inwardly of the circular arrangement formed by theassembly of reactors (2) and connected to central portions (10′, 11′)for radial connection and distribution of supply and evacuation lines(10, 11) of heat exchange fluid or fluids, the supply and evacuationlines (10, 11) being connected to said central connection anddistribution portions (10′, 11′) by the two sides or opposite surfaces(1′, 1″) of said module (1) and the configuration of said centralportions (10′, 11′) causing equivalent pressure drops and equivalentcirculation paths, on the one hand, for all the condensers (8), and, onthe other hand, for all the exchangers (7).
 6. Module according to anyone of claims 1 to 5, characterized in that each tubular body (3)comprises, on the one hand, at the level of its interface with its lowerprolongation (3″), an inwardly projecting ring (13) forming acircumferential abutment for blocking and sealed peripheral locking ofthe retention wall (4) for the material forming a synthesis support, forexample in the form of a disc-shaped filter, and on the other hand,several longitudinal conduits (14, 14′, 14″) for injection or passage,hollowed into the thickness of its wall and extending from the upperedge of said body (3), or at least from an upper portion of the body (3)located beyond the insulating structure (9), to the level of the portion(3′″) of the reaction chamber (3′) adapted to contain the medium and thereaction components, opening or not above said inwardly projecting ring(13) in an annular reinforcement (14′″) hollowed or formed in said wall.7. Module according to any one of claims 1 to 6, characterized in thateach base (6) for closing and emptying is constituted, on the one hand,by a bearing and sealing ring (15) mounted with locked adjustment andblockage in translation in the direction of the upper portion of thereactor (2) in question, for example against an inwardly projecting ring(13), in the tubular prolongation (3″) of the tubular body (3) of saidreactor (2) and provided with at least one circumferential rib (15′) forperipherally pinching the wall (4), on the other hand, by a body (16)for supporting and compressing the compressible porous retention wall(4) comprising, on the side directed toward said wall (4), a flatexternal circumferential bearing surface (16′) facing the rib or ribs(15′) of the ring (15) and a conical internal surface (16″) inclinedtoward a central evacuation opening (17) connected to an axial emptyingchannel (17′) hollowed into said body (16) and provided withprotuberances (18) for supporting the porous retention wall (4) and,finally, by a removable assembly (19, 20) for gripping the support andcompression body (16) against the bearing ring (15) and the connectionof a conduit or tube to the outlet of the emptying channel (17′). 8.Module according to claim 7, characterized in that the removablegripping assembly is comprised by a member (19) for guiding andtransmission of the pressure forces between a nut (20), preferablydouble screw-threaded and with a Z shaped cross-section, engaging byscrewing with a screw-threaded casing (21) secured to the prolongation(3″) of the tubular body (3) and the body (16) for support andcompression of the retaining wall (4), comprising a first hollowcylindrical portion (22) coming into contact, shape-matingly, againstthe rear surface of the support and compression body (16) by axiallyguiding a rear prolongation (16′″) of said body (16) on which is mounteda connection member (23) of a connection fitting (23′) of a conduit ortube adapted to be connected to the axial emptying channel (17′), and asecond cylindrical portion (22′) comprising a portion forming a washerinterposed between the first cylindrical portion (22) and a forceapplication surface (20′) of the nut (20) and a cylindrical portionprolonging said portion forming a washer and ensuring the guidance ofthe nut (20) relative to the piece (19) for guiding and transmittingforces and holding and guiding a proximal portion of the conduit or tubeconnected to the axial emptying channel (17′).
 9. Module according toany one of claims 1 to 8, characterized in that the injection head (5)comprises, on the one hand, an axial through passage (24) for mountingwith facility of rotation an element in the form of a rod (30′), on theone hand, a principal eccentric injection channel (25) connectedupstream to several supply channels (26, 26′, 26″) prolonging lateralsites (27) of connection of conduits or tubes for delivering fluid orfluids and opening into said injection channel (25) at places offsetalong this latter and, downstream, to channels (28) for radialdistribution from the downstream end of said injection channel (25) andopening adjacent the upper edge of the internal surface of the wall ofthe upper portion of the tubular body (3) of the reactor (2) inquestion, with regular distribution and substantially equivalentpressure drops, and, finally, by an eccentric channel (29) for expansionand evacuation of the gaseous fluids, opening in the lower surface ofthe injection head (5) and connected to a lateral site (29′) forcorresponding external connection.
 10. Module according to any one ofclaims 1 to 9, characterized in that each reactor (2) is provided with arotatable member (30) for mechanical agitation of the medium or mixturecontained in the reaction chamber (3′) in question, in the form of ahelix located at a small distance above the retaining wall (4) of thesynthesis support and mounted on the end of a rod (30′) forming a shaftor axle passing through the injection head (5) at the level of asuitable axial passage (24) and provided at its opposite end with anotched pulley (30″) or similar element for being driven by a member(31′) for transmission and distribution of movement, for example of thenotched belt type, interconnecting the pulleys (30″) of the agitationmembers (30) of the different reactors (2) of the module (1), thesynchronous rotation of the different agitation members (30) beingeffected by a variable speed motor (32) directly or indirectly drivingsaid transmission and distribution member (31′), and mounted, togetherwith said pulleys (30″) and said member (31′), as well as if desiredwith return pulleys and one or more belt tighteners (33, 33′) on asuitable support structure (34), removably, on the module (1). 11.Module according to any one of claims 1, 3, 5 or 10, characterized inthat the tubular bodies (3) of the reactors (2) with their prolongations(3″) are formed of a single piece in olytrifluorochlorethylene, as wellas the injection heads (5), in that the exchangers (7) and condensers(8), with their associated connection and distribution portions (10′ and11′) are made of nickel copper and in that the support structures (12and 34) are made of aluminum or an anodized aluminum alloy. 12.Apparatus for the synthesis of organic molecules in solid phase, withautomatic or semiautomatic operation, characterized in that it comprisesat least one module (1) according to any one of claims 1 to
 11. 13.Apparatus according to claim 12, characterized in that the module ormodules (1) are connected, on the one hand, at the level of the reactors(2), of the reservoirs (35, 36, 37, 38, 39, 40) for solvent or solvents,of compounds or elemental substances for syntheses, of synthesis supportsubstance, of reagents, of emptying, of recovery of waste, of expansionor the like, by means of a network for distribution and transferconstituted by a network of conduits or tubes (41′) interconnected withsingle path or multi-path units (41) of membrane valves, alsointegrating volumetric measures (42), the displacement of fluids in saidnetwork taking place under the action of gas under pressure, for exampleargon or nitrogen, whose use for pressurizing the different fluidsegments is controlled by predetermined sequential actuation of suitablevalve units (41), the times of opening said valves determining thevolumes transferred, and, on the other hand, at the level of theexchangers (7) and condensers (8), supply units (43, 43′) for heatexchange heating and cooling fluid or fluids through suitable supplycircuits formed of supply and evacuation lines (10, 11), said apparatusmoreover comprising a computer unit (44) for controlling and managingthe actuation of the different units of membrane valves (41) and theoperation of the supply units (43, 43′) for heat exchange gaseousfluids, by means of suitable interfacing and multiplexing circuits(44′), permitting control in terms of sequences of synthesis andselection between entirely automatic or semiautomatic operation, step bystep, of said apparatus.
 14. Apparatus according to claim 13,characterized in that the computer unit (44) also monitors the operationof the motor (32) driving the mechanical agitation members (30) in theform of helices, with control to at least two different speeds ofrotation, namely a low speed for suspending and homogenization of thereaction mixture and a high speed for the generation of a vortex adaptedto ensure de-compaction of the synthesis support.
 15. Apparatusaccording to any one of claims 12 to 14, characterized in that itcomprises several modules (1) and in that each module (1) is associatedwith a container (45) forming an exchange and distribution chamber,whose internal volume corresponds to the sum of the internal volumes ofthe reactors (2) of the module (1) with which it is associated, whoseconstruction is identical to those of said reactors (2) except for thesize of the constituent elements, being adapted to be connected to saidreactors (2) by a portion of the distribution and transfer networkcomprising at least one multi-path unit (41) with membrane valves and,as the case may be, provided with a mechanical agitation member (30),with a heat exchange (7), with a condenser (8) and with thermalinsulation over at least a portion of its tubular body (3).